diabetic nephropathy

1. PRESENTED BY
DR PRATEEK SINGH
PGY3 INTERNAL MEDICINE
INSTITUTE OF MEDICINE
DIABETIC KIDNEY DISEASE

2. introduction
 Diabetes is the leading cause of chronic kidney disease (CKD) and end-
stage kidney disease (ESKD) in developed countries.
 risk for development of DKD is equal in type 1 and type 2 diabetes -30%
to 40% will ultimately develop nephropathy.
 ESRD may be the most recognizable consequence of diabetic kidney
disease, the majority of patients actually die from cardiovascular
diseases

3.  Diabetic kidney disease" is a clinical diagnosis based upon
the presence of albuminuria, decreased eGFR , or both in
diabetes
 Albuminuria –
-it predicts the development of clinical nephropathy
-detected by measuring the albumin/creatinine ratio on a
spot urine sample (early morning preferred)

6.  Clinical outcomes in diabetic kidney disease are extremely
variable
 Earlier -moderately increased albuminuria was the earliest
clinically detectable biomarker of classical diabetic
glomerulopathy. And a decline in eGFR was thought to
occur after the development of moderately and then
severely increased albuminuria.

7.  Now - studies have shown that albuminuria may regress,
eGFR can occur and progress to advanced stages of
chronic kidney disease (CKD) before the onset or without
the development of albuminuria.
-Albuminuria may not be the earliest marker of DKD.
- e-GFR decline is of a greater prognostic importance.

8. Natural history
 Patients with type 1 or type 2 diabetes have a
paradoxically high GFR early in their disease course
 usually defined as GFR approximately 20 % or more
above that in age-matched, healthy controls without
diabetes.
 younger individuals - 120 to 140 mL/min/1.73 m2
older adults - 100 to 120 mL/min/1.73 m2

9.  earliest changes of renal function in in patients with type
1 & type 2 diabetes is an increase in GFR, or
hyperfiltration, which is accompanied by an increase in
renal size
 Followed by development of microalbuminuria.

10.  Moderately increased albuminuria (30 to 300 mg/g or
mg/day)- “microalbumniria” - forecasts a higher risk for
future kidney and cardiovascular disease in diabetic patients
,presence of such low-grade albuminuria should not
necessarily be considered "normal " if persistent.
 Severely increased albuminuria (>300 mg/g or mg/day) -
”macroalbuminuria”- forecasts an adverse prognosis.

12.  Average annual rage of decline in e-GFR of an otherwise
healthy individual is 0.5-1ml/min/1.73m2/year
 In diabetes it is >3ml/min/1.73m2/year, particularly in
patients with the following
1. Duration of diabetes> 10 years
2. Severely increased albuminuria
3. Low baseline e-GFR <60ml/min/1.73m2

13.  For every 10 fold increase in urine albumin excreation the
incidence of cardiovascular event is approximately 2.5x
higher
 For every halving of e-GFR it is approximately 2x higher

14. Non-albuminuric diabetic kidney disease
 Type 1 diabetes and reduced eGFR (<60 mL/min/1.73 m2), 7 to 24 %
are nonalbuminuric
 Type 2 diabetes and reduced eGFR, 39 to 52 % are nonalbuminuric
 women > men
 RAS inhibition
 Hypertension
 Dyslipidemia
 Smoking

15.  lower prevalence of retinopathy in nonalbuminuric compared with
albuminuric CKD could reflect mechanisms of nonalbuminuric
disease apart from microangiopathy
 Progression of diabetic kidney disease appears to be slower in
patients with nonalbuminuric disease

16. Risk factors
 High blood sugar (sustained hyperglycemia HBA1c > 8.6)
 High blood pressure
 Dyslipidemia
 Smoking
 A family history of diabetes and kidney disease
 Retinopathy

18. Pathogenesis
 complex and heterogeneous disease with numerous overlapping
etiologic pathways
 First degree relative with type 1 DN- risk of DN 83% vs 17%
 Hyperglycemia - cause afferent arteriolar dilatation via IGF,VEGF,
NO, Prostaglandin and Glucagon release AND efferent arteriolar
constriction via angiotensin II

20.  Glomerular hemodynamics
-diabetic milieu activates (RAAS) and numerous other downstream
mediators
-triggering -kidney hypertrophy,
increased renal plasma flow (RPF), and
increased filtration fraction (FF),
 which together result in an abnormally elevated (GFR)

22.  tubuloglomerular feedback - decrease in sodium delivery to the
macula densa in the early course of diabetes as the proximal tubule
hypertrophies and there is upregulation of the sodium-glucose
cotransporters (SGLT1 and SGLT2).
 afferent arteriolar tone is further decreased, thereby producing
increases in RPF, FF, and GFR.

23.  Oxidative stress and inflammation- Hyperglycemia as well as
insulin resistance and dyslipidemia cause increased formation of
AGE, which, upon binding to AGE receptors
- induces production of numerous cytokines via activation of nuclear
transcription factors, such as NF-kappaB
 Hyperglycemia causes increased shunting of glucose through non-
glycolytic pathways (polyol pathway) increasesing oxidative stress.

24. kimmelstiel wilson nodules
 Mesangial cell hypertrophy and matrix accumulation, hallmarks of
diabetic glomerulosclerosis (the acellular Kimmelstiel-Wilson lesion),
are mediated by the transforming growth factor-beta (TGF-beta)
system
 Described by kimmelstiel and wilson in 1936
 Eosinophilic nodules located in the center of peripheral glomeruli
 Microaneurysmal dilatation of associated capillaries
 Mesangiolysis and laminar organization of its debris
 Foam cells will surround

26. Proteinurea
 GBM widening d/t accumulation of type IV collagen and net reduction
in -vely charged heparin sulfate .
 Angiotensin II andTGF-beta induced by glucose suppress the
transcription of Nephrin which is a permeability controlling protein.4
 Angiotensin II andTGF-beta can also trigger apoptosis of podocytes
 The adhesion of podocytes to GBM can be reduced by Advanced
Glycation End products by suppressing migration of podocytes(via
reducing neuropilin 1) so that surving podocytes are prevented from
covering denuded areas of GBM

27.  Reduced adiponectin , that increases podocyte permeability to
albumin
 Reduced Endothelial thrombomodulin ,regulates activated protein
C (APC) formation which inhibits podocyte apoptosis

28. Tubulointerstitial fibrosis and
tubular atrophy
 TGF-beta is the central mediator in changing the phenotype of
tubular cells to become fibroblast like
 TGF-beta further induce fibroblasts to synthesize ECM proteins like
collagen and fibronectin
 Role of anemia even mild

31. diagnosis
 Albuminuria---in severe cases nephrotic range (ACR >30 mg/g
 Decrease in e-GFR (<60 )
 diabetes duration and presence of diabetic retinopathy

32. screening
 DM1 beginning 5 years after diagnosis
 annually for all patients with DM2 beginning at the time of diagnosis
 Confirmation of albuminuria or low eGFR requires 2 abnormal
measurements at least 3 months apart.

34. Indications of biopsy
 Absence of retinopathy (T1D)
 Albuminuria developing <5 years the onset of disease (T1D)
 Immunological markers or active urinary sediment
 Acute/sudden onset macroalbuminuria or the nephrotic
syndrome
 Nephritic syndrome
 Hematuria
 Rapid decline in renal function (>5ml/min/1.73m2/year)
 Significant reduction in eGFR (>30%) after initiation RAASi
 Acute Kidney Injury

35. Renal biopsy

36. Management
 Glycemic control
 Blood pressure control
 Angiotensin 2 control
 Proteinuria control
 Cholesterol control

37. Glycemic control
 Delay the development of albumin excretion
Stabilize the protein excretion in pts with UAE
Slow the progressive renal injury in Macroalbuminurea
May reverse early structural changes

38.  Metformin
 No hypoglycemia or weight gain • Inexpensive
• BUT:
– Renally-excreted
– Excess doses anorexia, diarrhoea
– Dose adjust to GFR: 2g to 250mg/day
– Protocol says
• eGFR 30 – 45 max dose ½ of required &titrate (3-6 mthly)
• cease when eGFR <30
– Risk of fatal lactic acidosis

39.  Glitazone
Av 1% fall in HbA1c as mono Rx or add-on
• Preserves beta-cell fn - use early
• Durable effect >3yrs
• BUT:
– delayed onset
– Average 4kg SC fat gain, visceral fat loss
– Oedema (Na+/H20, vasc. permeability)
– Expensive

40. SGLT-2 inhibitors
canagliflozin, dapagliflozin or empagliflozin in type 2 DM with
nephropathy with macroalbuminuria and e-GFR >=30 reduce risk
of kidney disease progression as well as incidence of CVD
Demerits of SGLT-2I
 Increased risk of lower limb amputation
 Increased urinary tract infection
 Increased genital fungal infection
 Cost
 Weak glucose lowering agents

41.  GLP-1 Receptor agonist
liraglutide OR dulaglutide in type 2 DM reduce a composite of renal
endpoints
 New onset macroalbuminuria
 Doubling of serum creatinine
 ESRD
 Renal death

42. Intensive vs conventional glycemic
control
 DiabetesControl and ComplicationsTrial (DCCT) compared the
effects of intensive glucose control with conventional treatment on
the long-term complications of type 1 diabetes (9 years)
 intensive therapy had a 35% to 45% lower risk for development of
moderately increased albuminuria.
 long-term risk for developing impaired GFR was lower by 50% in
patients treated for an average of 6.5 years with intensive glucose
control than among those treated with conventional therapy

43.  United Kingdom Prospective Diabetes Study (UKPDS)
 newly diagnosed patients with type 2 diabetes were assigned to
intensive management (HbA1c 7.0%) with a sulfonylurea or insulin or
to conventional management (HbA1c 7.9%) with diet alone
 relative risk reduction for the development of moderately increased
albuminuria was 24%.

44. trials
 ADVANCE study showed that intensive blood glucose control
(HbA1c 6.5% vs. 7.3%) yielded a 10% relative reduction in major
macrovascular and microvascular events, in particular a 21% relative
reduction in nephropathy.
 ACCORD trial, very tight glycemic control (lowering of HbA1c to
median of 6.4% vs. 7.5% with conventional control) was associated
with 22% increase in mortality from any cause and did not
significantly reduce major CV events.

47. Blood pressure control
 Once overt nephropathy develops, hypertension is an almost
universal finding and is associated with volume expansion and salt
sensitivity
 higher BP is associated with
-increasing albuminuria,
-more rapid progression,And increased risk for kidney failure,
-increased risk for fatal and nonfatalCV events

48.  BP goal
-130/80 (KDIGO/ADA/EASD) -140/90 (JNC-8,ESH-ESC)
 In patients with underlying CVD diastolic blood pressure should not
be lowered too much given concern of higher risk of coronary events
 UKPDS each 10 mm Hg Reduction in SBP was associated with 12%
risk reduction of diabetic complicaitions including DN
 Irbesartan Diabetic NephropathyTrial IDNT every 10 mm Hg
increase in baseline SBP was associated with enhanced risk of ESRD
or death of 6.7% but achieving systolic blood pressure below 120
was found to be associated with an increased risk

50. Angiotensin 2 control
 Evidence: ACEI in type 1
ARB in type 2
 Irrespective of BP control- IDNT trial and RENAAL trial
Renal protection with ACEI
 Diabetic Retinopathy CandesartanTrials (DIRECT) trial, which
included patients with normotensive and normoalbuminuric both
T1DM &T2DM found to have no effect on the development of
moderately increased albuminuria.

51.  The Bergamo Nephrologic DiabetesComplicationsTrial (BENEDICT),
which randomized patients with hypertension, normoalbuminuria
 verapamil, trandolapril, or a combination of verapamil plus
trandolapril, showed less progression to moderately increased
albuminuria
 Renal protection with ARBs
-Lower Systemic Blood Pressure
-Lower Intra glomerular Pressure and filtration rates
-Reduce Proteinuria

52.  Inhibit non Heamodynamic effects of Angiotensin on various cell
types
 Reduction in Cytokine and Growth factor synthesis e.g.TGF β
 Mesangium:
-Reduced Cell proliferation
-Hypertrophy
-Matrix Expansion
 Reduction in Oxidative Stress
 Inhibit macrophage activation, proliferation and migration

53. Combined ACEI and ARB
 Not recommended
 Decrease proteinuria but do not prevent progression of renal disease
or death
 Rather has increased rate of serious adverse events
 OngoingTelmisartan Alone and in Combination with Ramipril
Global End-pointTrial (ONTARGET) -which included diabetic and
nondiabetic patients with CV risk, failed to show improved CV
outcomes Instead, it showed more rapid loss of kidney function in
some patients

54.  Veterans Affairs Nephropathy in Diabetes study (VA NEPHRON-
D) tested combination therapy with ACE inhibitor and ARBs in
patients with type 2 diabetes with overt nephropathy.
 no difference in the primary end-point of CKD progression or death
 increase in hyperkalemia and doubling of the risk for acute kidney
injury

56. Nondihydropyridine calcium channel
blockers
 Diltiazam and verapamil slow most of the morphologic features of
diabetic renal disease
 But diltiazem alone was found to be associated with increased
tubulointerstitial fibrosis and global glomerulosclerosis
 This effect was found to be prevented by combined therapy with
ACEI
 Add after BP control inadequate with ACEI/ARB+ diuretic
 Avoid with patient already under a beta blocer
 DihydropyridineCCB like amlodipine may be added in patients
already under beta blocker

57. Reducing intra-glomerular pressure
 Control of hypertension
 Dietary protein restriction
0.6g/kg/day slowed GFR decline by 60-75%
Another study decline was same but incidence of death and onset of
ESRD was significantly reduced
Underlying mechanism unknown

58. Low protein diet
Potential problem associated with low protein diet
Enhanced protein breakdown induced by insulin deficiency
Compliance as there is concorrunt fat and carb restriction in DM patients
 Dietary salt restriction which may blunt the antiproteinuric effects of
Angiotensin inhibitors therefore pt on ACEI/ARB who don’t have
sufficient reduction in proteinuria despite appropriate BP goals should
be instructed to take a low sodium diet restrict to<70mEq/day difficult
therefore restrict to @least <=100mEq/day
If low sodium diet is not possible add a diuretic
Target improvement in proteinuria is at least 60% from the baseline value

59. diuritics
 Diuretics do not have an antiproteinuric effect despite reducing BP
 Irrespective of BP control, Mineralocorticoid RA appear to reduce
proteinuria when used alone and have additive effect when used
with ACEI or ARB in both type 1 and 2 diabetes

60. Hyperlipidemia
 Common in diabetics
 Commoner with the development of renal insufficiency
 Aggressive lipid lowering is recommended in all diabetics as it is
considered a coronary heart disease equivalent
 Promote systemic atherosclerosis
 Contribute to the development of glomerulosclerosis in CKD

62. Novel treatment for DKD
 TGF-beta contribute to cellular hypertrophy and collagen synthesis
 TGF-beta inhibitors are novel agents under study

64. Take home message
 Early detection and diagnosis of albuminuria and fall in eGFR
 Differentiate from non DKD and when to perform biopsy
 Intensive glycemic control
 Early initiation of ACEI andARB delays development of albuminuria
and preserves decline in GFR
 Newer agents needs more study

65.  Thankyou